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Aberrant overexpression of HOTAIR inhibits abdominal adipogenesis through the epigenetic remodelling of genome-wide DNA methylation and transcription

ABSTRACT: Objective: Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long non-coding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator, with fat depot-specific expression between abdominal subcutaneous adipose tissue (SAT) and gluteal SAT. HOTAIR locates closely with HOXC13, known to strongly associated with human fat distribution. Here, we examined the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis, and hypothesized that HOTAIR-mediated DNA methylation is correlated with transcriptome changes, leading to the regulation of specific genes and the functional pathways. Methods: The expression level of HOTAIR was compared among different fat-depots collected from six healthy, five severe obese, and five uremic subjects, and was correlated with dual-energy x-ray absorptiometry (DXA) defined regional adiposity. The human immortalized preadipocyte was used to assess the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis. The integrative analysis of reduced representation bisulfite sequencing (RRBS) and RNA-sequencing was performed to identify putative genes that are epigenetically regulated by HOTAIR, and the associated signaling pathways. HOTAIR-repressed genes were further validated using RNA/chromatin immunoprecipitation with real-time qPCR and correlated with human body fat distribution. Results: We found that the expression of HOTAIR was high in gluteal SAT, and low in arm/abdominal SAT and visceral (omental) adipose tissue. It could be aberrantly increased in uremic arm SAT. Notably, in severe obese subjects we found that HOTAIR is lowly expressed in abdominal SAT correlating with a higher abdominal adiposity, whereas in uremic patients HOTAIR is highly expressed in arm SAT correlating with lower arm adiposity. HOTAIR overexpression in human immortalized abdominal preadipocyte remarkably suppresses the in vitro adipogenesis. Overall the differentially methylated genes were functionally enriched for nervous system development. We specifically identified 10 HOTAIR-mediated genes showing strong changes of DNA methylation associated with gene expression during abdominal adipogenesis, suggesting potential epigenetic regulation. Two HOTAIR-repressed genes, SLITRK4 and PITPNC1, were further highlighted and validated; presenting an obesity-driven fat-depot specific expression pattern positively correlated with the central body fat distribution. Conclusions: Our study indicated that HOTAIR is an important regulator for abdominal adipogenesis via intricate DNA methylation likely to associate with transcriptional regulation of specific genes, such as SLITRK4 and PITPNC1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186159 | GEO | 2022/04/20

REPOSITORIES: GEO

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Project description:Visceral fat (VF) and subcutaneous fat (SF) are developmentally different tissues with different gene expression. Islet-1 (ISL1), a LIM-homeobox transcription factor with important developmental and regulatory function in islet, neural, and cardiac tissue, is virtually absent in SF but substantially expressed in the stromovascular [preadipocyte containing] fraction of VF; expression correlates negatively with adiposity in rodents and man. ISL1 expression is transiently increased in 3T3-L1 preadipocytes during early differentiation, suggesting a functional role. To examine the role of ISL1 in adipogenesis, we tested whether retroviral overexpression of ISL1 in 3T3-L1 preadipocytes affected their ability to differentiate into mature adipocytes. Terminal differentiation was assessed by Oil Red O [lipid droplet] staining and by immunoblot detection of adipocyte marker proteins, including aP2 and GLUT4. ISL1 significantly inhibited lipid droplet formation, reduced lipid accumulation (about 80% inhibition, p<0.05), and substantially inhibited aP2 and GLUT4 expression. ISL1 did not inhibit expression of C/EBPb and C/EBPd after induction of differentiation, but reduced PPARg and C/EBPa by >50% at both mRNA and protein level. In addition, the PPARg agonist, rosiglitazone, substantially rescued ISL1 inhibited adipogenesis in the absence of exogenous PPARg, and fully rescued in the presence of exogenous PPARg. In summary, ISL1 overexpression inhibited fat droplet formation, lipid accumulation, and adipocyte-specific gene expression; there was accompanying inhibition of C/EBPa, PPARg and downstream gene expression. We conclude that ISL1 overexpression inhibited adipocyte differentiation by inhibition of PPARg regulated gene expression. As abdominal obesity strongly correlates with insulin resistance, and cardiovascular risk, ISL1 up-regulation may impact abdominal obesity and its concomitant metabolic derangements. Total cellular RNA was isolated from 3T3-L1 cells expressing Flag-ISL1 or not at 48 h following treatment with differentiation cocktail. Individual RNA from biological triplicates was used for microarray analysis.

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Aberrant overexpression of HOTAIR inhibits abdominal adipogenesis through the epigenetic remodelling of genome-wide DNA methylation and transcription

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